The present invention relates to the use of benzazepin-N-acetic acid derivatives which contain an oxo group in the a position to the nitrogen atom and are substituted in the 3 position by a 1-(carboxyalkyl)-cyclopentyl-carbonyl-amino radical, and of their salts and biolabile esters, in particular for the prophylaxis and/or treatment of damage to the heart in larger mammals and in particular humans which is caused by oxidative-toxic, in particular cardiotoxic, doses of medicaments or chemicals, and to the preparation of medicaments suitable for this prophylaxis and/or treatment. Generally, the invention also relates to the use of the afore-mentioned benzazepin-N-acetic acid derivatives for adjuvant treatment in therapies in which medicaments having oxidative-toxic, and in particular cardiotoxic, side-effects are used. Preferably, the invention relates to the prophylaxis and treatment of damage to the heart, in particular to the myocardium, which may occur during cytostatic chemotherapy.
It is known that the cytostatic agents used in the chemotherapy of malignant tumours may have cardiotoxic properties as an unwanted side-effect. Thus, some antibiotics are also used in cytostatic therapy which, owing to their generally toxic properties, cannot be used for the treatment of bacterial infections. These include, for example, the anthracyclines isolated from streptomyces species, which are among the important more recent developments in the field of cytostatic agents. However, the clinical usability of the anthracyclines is limited by their more or less greatly marked cardiotoxicity. The cardiotoxicity in this case is correlated to the total dose administered, and is frequently irreversible. Presumably, the heart damage and the cytostatic effects of these antibiotics are based at least in part on the membrane action thereof, by means of which the membrane fluidity and permeability is increased by the binding of the antibiotic to components of the cell membrane. Furthermore, oxidative damage may also be considered as an additional cause.
Typical antibiotics used in cytostatic therapy include the anthracyclines daunorubicin and the prodrug thereof, zorubicin, doxorubicin (adriamycin) and epirubicin, and the synthetic antibiotic mitoxantrone.
Benzazepin-N-acetic acid derivatives which contain an oxo group in the a position to the nitrogen atom and are substituted in the 3 position by a 1-(carboxyalkyl)-cyclopentyl-carbonyl-amino radical, and their salts and biolabile esters fall within the scope of protection of benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid derivatives described in Waldeck et al., U.S. Pat. No. 5,677,297 (=DE 195 10 566), which contain an oxo group in the a position to the nitrogen atom and are substituted in the 3 position by a 1-(carboxyalkyl)-cyclopentyl-carbonyl-amino radical, and which have NEP-inhibiting effects on the heart. The benzazepin-N-acetic acid compounds used within the scope of the present invention may be prepared using the process described in Waldeck et al., U.S. Pat. No. 5,677,297, the entire disclosure of which is incorporated herein by reference.